The Known chemotherapeutic techniques for cancer have several hindrance factors, e.g., side-effects to normal cells and tolerance to anti-cancer drugs. One method to overcome the side-effects to normal cells is known as targeted therapy which has relatively less side effects than the use of existing anti-cancer drugs. Some drugs used in the targeted therapy exhibit the effect of increasing viability in progressive colorectal cancer, breast cancer and lung cancer when being combined with other chemotherapies. However, the targeted therapy still has many problems.
For example, drugs used in the targeted therapy interfere with specific targeted molecules needed for carcinogenesis, and thus exhibit effects only for patients having the specific targeted molecules even in the same kinds of cancer. Therefore, in order to apply the targeted therapy more effectively, it is required to establish indexes to predict the effect of the targeted therapy in advance. Also, the continuous use of the targeted therapy may cause tolerance. Accordingly, there is a need to develop a novel therapeutic agent capable of raising treatment effects with overcoming the tolerance to drugs, despite of the development of the targeted therapy.
Calcium plays a critical role as an intracellular signal, and controls various cell processes, of which calcium appears to play an important role in cell growth. For example, calcium signaling is required for cell cycle progression from G1 phase to S phase during mitosis, and the depletion of intracellular calcium arrests the cell cycle in the transition of G0/G1 into S phase. Regulation of the intracellular calcium amount has been proposed to be via a T-type calcium channel. Lined with this proposition, it has recently been reported that T-type calcium channel blockers (CCBs) inhibited cellular proliferation [McCalmont, W. F., et al., Bioorg. Med. Chem. Lett. 2004, 14, 3691-3695; McCalmont, W. F., et al., Bioorg. Med. Chem. 2005, 13, 3821-38391]. Therefore, selective T-type CCBs could be another tool to treat cancer where the cell cycle is abnormal. Korean Patent Application Publication No. 10-2008-0099108 discloses a 3,4-dihydroquinazoline derivative of the following formula (A) having excellent T-type calcium channel blocking effect and anti-cancer activity.

wherein,
R1 is NR4(CH2)nNR5R6, where R4 is hydrogen or C1-C5 lower alkyl, n is an integer of 4 to 6, R5 and R6 are each independently hydrogen or C1-C5 lower alkyl, or taken together with the nitrogen atom to which they are attached form a 4 to 6-membered heterocycle;
R2 is 4-biphenylyl;
R3 is benzylamino, 4-aminobenzylamino or 4-fluorobenzenesulfoneaminobenzylamino.
The 3,4-dihydroquinazoline derivative of formula (A) just directly exhibits strong cytotoxicities against cancer cells, but has not been studied as a combination for reinforcing the efficacy of existing anti-cancer drugs.